AMP-activated protein kinase beta-1-containing complex (AMPK-beta-1)

AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme complex consisting of an alpha catalytic subunit and regulatory beta and gamma subunits, serving as a master regulator of cellular energy homeostasis (Hardie et al., 2012, Chem Biol). The beta-1 (beta-1) subunit, encoded by the PRKAB1 gene, acts as a scaffold for the complex and contains a carbohydrate-binding module (CBM) that senses glycogen levels (UniProt P80331). AMPK beta-1-containing complexes are predominantly expressed in the liver and are critical for regulating lipid and glucose metabolism, making them prime targets for treating metabolic disorders (Hawley et al., 2012, Science). Small molecule activators, such as salicylate and A-769662, bind to the Allosteric Drug and Metabolite (ADaM) site located at the interface of the alpha-kinase domain and the beta-CBM (Cool et al., 2006, Cell Metab). Activation of these complexes promotes catabolic pathways like fatty acid oxidation and glucose uptake while inhibiting anabolic processes such as lipid synthesis. Consequently, targeting beta-1-containing AMPK complexes is a therapeutic strategy for type 2 diabetes, non-alcoholic steatohepatitis (NASH), and obesity, with the potential advantage of avoiding cardiac side effects associated with the beta-2 isoform (Myers et al., 2017, Science).

Other names

PRKAB1-containing AMPKAMPK beta 1 complex5'-AMP-activated protein kinase subunit beta-1 complexAMPK-beta1

Direct allosteric activation by binding to the Allosteric Drug and Metabolite (ADaM) site, which is formed between the alpha-subunit kinase domain and the beta-subunit carbohydrate-binding module (CBM), leading to increased catalytic activity and protection of the Thr172 phosphorylation site from phosphatases (Hardie et al., 2016, Nat Rev Mol Cell Biol).